Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin

Matteo Di Piazza, Ute Koch, Freddy Radtke
Public Library of Science, 2010
Article

Résumé

BACKGROUND: The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth. METHODOLOGY AND PRINCIPAL FINDINGS: To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia. SIGNIFICANCE: Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.

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https://infoscience.epfl.ch/record/150527?ln=fr

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Matteo Di Piazza, Ute Koch, Freddy Radtke
Public Library of Science, 2010
Article

Résumé

Official source

https://infoscience.epfl.ch/record/150527?ln=fr

À propos de ce résultat

Concepts associés (19)

Concepts associés

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Publications associées (29)

Publications associées

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The Cell Differentiation Status Influences the Outcome of Notch-Induced Malignancy

Caroline Poisson

The Notch signaling cascade is a well conserved pathway that regulates many aspects of embryonic development and plays a crucial role in the differentiation process and tissue homeostasis in multiple organs of adult species. Several human pathological disorders, including cancer, arise as a consequence of the deregulation of the Notch signaling pathway. Notch deregulation, up to date, has been best characterized in acute T-cell lymphoblastic leukemia (T-ALL). Indeed, in T-ALL pediatric patients activating Notch1 mutations have been identified in more than 50% of the cases. Increased knowledge of the mechanisms underlying T-ALL development and maintenance is clearly needed as one out of 5 patients with T-ALL has a very poor prognosis. Moreover, the high toxicity of chemotherapeutic regimens has been associated with elevated risks of developing severe secondary health problems. In the present study, we characterized the role of Notch in T-ALL induction and maintenance. Using transgenic mouse models, we could demonstrate that the oncogenic potential of Notch is dependent on RBP-Jκ transcriptional activity. Indeed, the canonical Notch signaling pathway, mediated by the RBP-Jκ transcription factor, is essential for both Notch-mediated T-ALL induction and maintenance, as well as for the induction of a Notch-mediated lymphoproliferative disorder. Moreover, constitutive overexpression of Notch1 at discrete developmental stages within the hematopoietic system, led us to identify a correlation between the differentiation status of a cell, within the hierarchy of the hematopoietic tree, and its sensitivity to Notch1-induced transformation. We demonstrated that forced Notch1 expression in hematopoietic stem cells was not sufficient to induce T-ALL. Nevertheless, aberrant Notch1 expression in the bone marrow resulted in the development of a lethal lymphoproliferative disorder. Overexpression of Notch1 in thmus at the DN2 to DN3 stage of T-cell delvelopment generated an aggressive transplantable T-ALL with important metastatic potential. This suggested that progenitors already committed to the T-cell lineage are highly susceptible to Notch-mediated transformation, which is relevant to the human disease. Nevertheless, forced Notch1 expression after the β-selection checkpoint in the thymys, was no longer sufficient to induce transformation of late DN3 to DN4 thymocytes. We therefore established a murine genetic system that allowed us to dissect the mechanisms of aberrant Notch1 signaling in a lymphoproliferative disorder and a true T-ALL model. We were able to assess the genetic signature that is involved in the transplantability and metastatic potential of leukemic cells and generated a list of candidate genes implicated in these processes. In addition, we correlated genes identified in our murine models with genes associated as well in human T-ALL profiles to identify genes implicated in T-ALL pathogenesis in both mouse and human.

EPFL2011

Chargement

Chronic lymphocytic leukemia (CLL) is a B cell malignancy and represents the most common leukemia in adults within the Western world. This disease mainly affects the elderly, with a median age of diagnosis over 70. The disease course is highly variable among patients; some experience rapidly progressing leukemia which becomes resistant to treatment, while others bear indolent disease and will die from other causes. Morbidity correlates with the chromosomal aberration and mutational burdens observed in patients. NOTCH1 gain-of-function mutations are among the most frequently observed mutations in patients. They are found in 10-15% of CLL patients at diagnosis and their prevalence increases up to 30% in late-stage disease. Many correlative studies have shown that patients harboring NOTCH1 mutations exhibit a reduced survival compared to those with unmutated NOTCH1. Although the presence of NOTCH1 mutations is associated with poor prognosis, it remains unclear by which mechanisms NOTCH signaling might influence disease development. Here, we assessed the role of Notch signaling in CLL using genetic loss- and gain-of-function studies in a transgenic mouse model (IgH.TEµ) that faithfully recapitulates human disease phenotypes. We found that B cell specific knock-out of RBP-J significantly decreased prevalence of CLL induction in RBP-J depleted mice compared to control animals. Reciprocal Notch gain-of-function experiments revealed that mice with enforced Notch1 signaling had an earlier CLL onset compared to controls. Recipients of sorted CLL-like cells over-expressing Notch1 had reduced survival compared to control infusion. Taken together, these genetic studies strongly suggest a role for Notch signaling in disease initiation. To study the molecular mechanisms by which Notch1 signaling enhanced CLL aggressiveness, global gene expression as well as global epigenetic analyses were performed on sorted CLL-like cells from Notch1 gain-of-function and control animals. Cell cycle related pathways in gene set enrichment analysis were the most significantly induced signature in the Notch1 gain-of function CLL-like cells compared to control CLL-like cells. This result was further confirmed by functional cell cycle assays in vivo, strongly suggesting that Notch signaling accelerates CLL initiation by promoting proliferation.

EPFL2020

Chargement

Notch signaling in the immune system

Nicolas Fasnacht, Freddy Radtke

The Notch signaling pathway regulates many aspects of embryonic development, as well as differentiation processes and tissue homeostasis in multiple adult organ systems. Disregulation of Notch signaling is associated with several human disorders, including cancer. In the last decade, it became evident that Notch signaling plays important roles within the hematopoietic and immune systems. Notch plays an essential role in the development of embryonic hematopoietic stem cells and influences multiple lineage decisions of developing lymphoid and myeloid cells. Moreover, recent evidence suggests that Notch is an important modulator of T cell-mediated immune responses. In this review, we discuss Notch signaling in hematopoiesis, lymphocyte development, and function as well as in T cell acute lymphoblastic leukemia.

2010

Chargement

The Cell Differentiation Status Influences the Outcome of Notch-Induced Malignancy

Caroline Poisson

EPFL2011

EPFL2020